The invention generally relates to the area of mass spectroscopic analysis and more particularly to linear ion traps as stand-alone mass spectrometers, as part of MS-MS tandems and as a source for time-of-flight mass spectrometers. More particularly, the invention is particularly concerned with providing mass selective ion sampling out of a linear ion trap in combination with soft conditioning of the output ion beam.
There are multiple examples in the prior art of linear ion trap mass spectrometers (IT MS), as stand-alone mass spectrometers, as a source for time-of-flight mass spectrometers (TOF MS) and as a part of tandem mass spectrometers (MS-MS). Linear ion traps and ion guides of various types are suggested to serve as ion accumulation devices, ion conditioning devices, pulsing devices and fragmentation cells for TOF MS, as well as devices for trapping ions after TOF MS for subsequent fragmentation, storing, conditioning and mass analysis. In the prior art, the trap devices are either ion trap mass spectrometers exhibiting a high mass resolving power, but poor ejected ion beam characteristics or they are devices exhibiting appropriate ion beam conditioning, but no mass selection features.
1. Ion Trap Mass Spectrometers
Ion trap mass spectrometers (IT MS) have been widely used since the 1990's. Most mature ITMS are based on Paul three-dimensional (3-D) quadrupole ion traps [W. Paul, H. P. Reinhard and U. von Zahn, J. Physik, V. 152 (1958) 143]. Such traps are composed of a ring electrode and two cap electrodes. A radio frequency (RF) signal is applied to the ring electrode while DC and weak AC signals are applied to the cap electrodes. The trap is filled with helium at about 1 mtorr gas pressure to dampen ion motion and to prevent excitation of unwanted resonance ion motions. Ions are generated within an external ion source, like an Electron Impact (EI), Electrospray, APCI or MALDI ion source and are injected into the trap, either continuously or in a pulsed manner.
Multiple strategies of ion manipulation have been developed [Syka, J. E. P. Commercialization of the Quadrupole Ion Trap. March, R. E.; Todd, J. F. J., Eds. Practical Aspects of Ion Trap Mass Spectrometry, V. 1: Fundamentals of Ion Trap Mass Spectrometry, 1. CRC Press: Boca Raton, Fla., 1995; 169-205]. Ramping of the RF signal amplitude allows resonance ejection with sequential ejection of ions. Depending on the frequency and amplitude of the AC signal, such ejection occurs either on the edge of ion stability or within the region of ion stability. Correlation of the ion signal with the RF amplitude provides mass spectrometric measurement of the entire contents of the ion trap. In other words, the trap is capable of parallel analysis of all ion species in a wide mass range. Slight distortion of the quadrupole field (introduction of an octupolar field component) is known to improve resolution of resonant ejection and to provide mass resolution in the order of R=10,000. Excitation of secular ion motion by an AC signal allows the rejection of unwanted ion species, and thus, an isolation of ions of interest within the trap. The isolated ions could be further excited by an AC signal to induce collisional fragmentation. A sequence of isolation, fragmentation and mass analysis by resonant ejection allows a multistage MS-MS analysis, which could be repeated multiple times to provide a so-called MS to the n (MSn) analysis.
Paul 3-D ion trap mass spectrometers suffer multiple limitations, like low efficiency of ion injection (few percents), low space charge capacity (about 300 ions), high cut-off m/z at fragmentation (⅓ of upper mass), and slow and soft collisional fragmentation, which produces limited sequence information. Parameters of an ion trap have been substantially improved with the introduction of linear ion traps with radial ion ejection as disclosed in U.S. Pat. Nos. 5,420,425 and 5,576,540. The trap is made of three quadrupole segments. A radio frequency field is applied between rods in all three segments to confine ions in a radial direction. A repelling DC bias is applied to side segments to trap ions axially. Helium at 1 mtorr gas pressure is used to dampen ion motion. An AC signal is used to excite radial motion in one preferred direction, such that excited ions leave through slots in two opposite rods. Distortion of the rod geometry provides an octupolar component of the RF field to improve the resolution of resonance ejection. The strategies of MS and MSn analysis are similar to those implemented in 3-D traps. The space charge capacity of a linear trap is 10-30 fold better. The efficiency of axial ion injection is brought close to unity. Novel methods of ion excitation provide sequence information comparable to CID fragmentation in 3-Q and Q-TOF instruments (industry standard).
A linear ion trap with mass selective axial ejection (MSAE) assisted by resonance excitation has been suggested in U.S. Pat. Nos. 6,177,668 and 6,194,717. A linear quadrupole is surrounded by apertures with a repelling DC potential. The trap is held at 10−5 torr gas pressure. Ions are generated in an external ion source and are accumulated within the trap. A repelling DC potential at the exit aperture prevents the ions from leaving the trap. The ions of interest are excited by an AC signal which matches the frequency of ion secular motion. An ion cloud expands radially and in the vicinity of the exit aperture it reaches an instability zone (cone of instability) where radial and axial RF fields are coupled and the RF field is capable of ejecting ions over the weak (2V) repelling DC barrier. Thus, ions of interest are sampled out of the trap while leaving the rest of the ions within the trap. Scanning of trap parameters (RF amplitude, AC frequency, small DC field between rods) allows sequential ejection of various m/z components used for mass analysis. The trap allows efficient ion injection (close to unity), moderate efficiency of ion ejection (15-20%) and mass resolving power up to 5000. The trap is suggested to be coupled with a quadrupole or a TOF mass spectrometer for MS-MS analysis.
The above-described ion traps—three-dimensional Paul trap, linear ion trap with radial ejection and linear ion trap with MSAE—are all primarily designed for mass analysis with high resolving power and are based on a so-called resonance ejection. However, resonant ejected ions are unstable (because of high energy collisions in the trap during excitation and ejection) and possess large energy and angular spreads. This does not prohibit immediate detection of ions. However, this does affect coupling between ion traps and other mass spectrometric devices (such as a fragmentation cell, ion reaction cells, accumulating and transfer ion guides, ion mobility spectrometers, and other mass analyzers), ion soft deposition on surface, and ion gaseous accumulation for spectroscopic analysis or for gaseous ion reactions.
Besides mass analysis, there are multiple alternative applications of ion traps. For example, ion traps are used to store ions for the purpose of gaseous ion reactions [E. Teloy and D. Gerlich, Integral Cross Sections for Ion Molecular Reactions, The Guided Beam Technique, in Chemical Physics, v. 4 (1974) 417-427 and U.S. Pat. No. 6,140,638] and ion optical spectroscopy [J. D. Prestage, G. J. Dick and L. Maleki, New ion trap for frequency standard applications, J. Appli. Phys., v.66 (1989) 1017]. McLuckey et. al. employ 3-D and linear ion traps to reduce the charge of positive multiply-charged Electrospray ions [S. A. McLuckey, G. E. Reid, and J. M. Wells, Ion Parking during Ion/Ion Reactions in Electrodynamic Ion Traps, Anal. Chem. v. 74 (2002) 336-346]. Protein and large peptide multiply-charged ions are stored and exposed to a flux of negative reactant ions to reduce the charge, thus simplifying spectra interpretation. British Patent Nos. 2 372 877, 2 403 845 and 2 403 590 disclose multiply-charged ions stored in a trap to expose them to thermal electrons to produce an electron-capture dissociation (ECD) which provides rich sequence information.
There are multiple ion guide devices which do not have any mass separation features. Linear multipoles (usually quadrupoles) comprise a set of linear rods. Two opposite phases of radio frequency (RF) signals are applied to rods alternating between adjacent rods. As a result, the net RF field is zero on the axis of the guide and rises near rods. The inhomogeneous RF field retains ions in radial direction pushing them towards the center of an ion guide. Ion guides are gas filled at gas pressure P about 10 mtorr and have sufficient length L for ion collisional dampening (P*L>200 cm*mtorr) in the ion interface [U.S. Pat. No. 4,963,736] and in a fragmentation cell [U.S. Pat. No. 6,093,929]. Ion dampening is used for conditioning of the ion beam, i.e., for substantial improvement of ion beam characteristics. Ion guides with collisional dampening primarily serve for ion transport or ion accumulation. They are also employed as a fragmentation cell in tandem mass spectrometers. A weak axial field could be introduced within the ion guides [U.S. Pat. Nos. 5,847,386 and 6,111,250] to control axial velocity and time of ion refreshing. External electrodes (usually referred to as “auxiliary electrodes”) are used to impose an external field which partially penetrates between rods, thus modifying an axial potential distribution. A dragging axial field is used to accelerate ion transfer through a guide or fragmentation cell. An external field may be also used to provide local wells and weak traps.
Linear ion guides are readily convertible into linear ion traps by using any means to repel ions axially at entrance and exit ends. The most common method of ion trapping within ion guides employs a retarding DC potential at the exit apertures to plug ions on the ion guide ends [Prestage, same ref.]. Pulsing the potential on such apertures allows ion beam modulation and creates slow ion packets (microsecond scale) for injection into 3-D ion trap [U.S. Pat. No. 5,179,278] or TOF MS [U.S. Pat. No. 6,020,586]. Radiofrequency plugging has been used for trapping ions of both polarities [McLuckey ASMS 2005]. Such a trap is used, for example, to carry ion-ion reactions.
2. Time-of-Flight Mass Spectrometers Using Ion Traps
A variety of ion traps and ion guides have been used in combination with a TOF MS, and particularly with a TOF MS having an orthogonal ion injection (O-TOF MS) [PCT Patent Application No. WO 9103071 by Dodonov et. al.]. O-TOF MSs are widely used as stand-alone instruments and as a part of MS-MS tandems like Q-TOF and ITMS-TOF. O-TOF MSs provide a unique combination of high speed, sensitivity, resolving power (resolution) and mass accuracy. The method of orthogonal pulsed acceleration allows converting a continuous ion beam (like one generated in the intrinsically continuous ESI, APCI, EI and ICP ion sources) into frequent ion packets with a very short time spread (few ns), suitable for time-of-flight mass spectrometers. However, the efficiency of the conversion (so-called duty cycle) is limited. In singly-reflecting TOFs (so-called reflectrons) the duty cycle of an orthogonal accelerator is known to be in the order of K=10-30% for ions with highest m/z in the spectrum and dropping proportional to square root of m/z for smaller m/z ions.
Ion guides with collisional dampening in bath gas [U.S. Pat. Nos. 4,963,736 and 6,093,929] has been successfully applied to an o-TOF MS. The ion guide, usually a quadrupole guide at sufficient gas pressure P and length L (PL>200 cm*mtorr), improves spatial and energy characteristics of the continuous ion beam which helps improve the resolution and sensitivity of the o-TOF MS [Chernushevich I. V., Ens W., Standing K. G. In Electrospray Ionization Mass Spectrometry: Fundamentals, Instrumentation & Applications, Cole R (ed.). John Wiley & Sons: New York, 1997; Chapter 6, 203].
A scheme of storage and pulsed release of ions from an ion guide into an orthogonal acceleration stage is introduced by Dresch et. al. [U.S. Pat. No. 6,020,586] to improve the duty cycle. However, because of time-of-flight separation of ion packets in front of the orthogonal acceleration stage, the duty cycle is improved within a narrow mass range (depending on the time delay between ion release and pulsed acceleration) while it becomes zero for the rest of the ions. The method is useful when monitoring single secondary ion species in tandem mass spectrometers [U.S. Pat. No. 6,507,019], but provides marginal benefits in a single stage mass spectrometer. To recover a full spectrum one has to vary the delay in a series of pulses, thus losing an advantage of locally improved duty cycle.
U.S. Patent Publication No. 2004/0232327 discloses a method of ion bunching in front of an o-TOF MS. A time-dependent retarding or accelerating field is applied in the region between a pulsed ion source and the orthogonal accelerator. This method, however, inevitably leads to ions of different m/z gaining essentially different kinetic energies and thus leaving the orthogonal accelerator under essentially different angles. Such angular spread requires large-size detectors in conventional o-TOF MSs and it is unacceptable for multireflecting TOF MSs.
A number of schemes suggest an ion trap as a source for direct ion pulsing into a TOF MS. A 3-D trap is used for ion storage in Lubman S. M. Michael, B. M. Chien and D. M. Lubman, Anal. Chem. V. 65, (1993) 2614 and B. M. Chien, S. M. Michael and D. M. Lubman, Anal. Chem. v. 65 (1993) 1916 and a linear ion trap with radial ejection is suggested in Franzen. Recent studies of Kozlov et. al., [Linear Ion Trap with Axial Ejection As a Source for TOF MS, extended abstract, ASMS 2005, www.asms.org] have shown multiple problems of such schemes. Slow collisional dampening (at least 10 ms at 1 mtorr gas pressure) reduces a pulsing rate below 100 Hz (which is 100 times lower compared to a conventional o-TOF MS) and increases a spike load onto the TOF detector and data system. Because of a long cooling time, a substantial space charge is accumulated in the trap (1 to 10 million of ions), which deteriorates the ion cloud parameters and affects both mass resolution and mass accuracy of the TOF MS. Thus, ion trap pulsed sources are inferior to a conventional method of orthogonal acceleration out of a continuous ion beam.
The ion source schemes should be also reconsidered if applied to recently introduced multireflecting TOF MSs, which are very attractive for reasons of high resolving power above 105 [Toyoda M., Okumura D., Ishihara M., Katakuse I., Multi-turn Time-of-flight Mass Spectrometers With Electrostatic Sectors, J. Mass Spectrom, 2003, V.38, p. 1125-1142], [Hasin et. al. JTP]. Co-pending PCT Patent Application No. WO 2005/001878 describes an MR-TOF with a planar geometry and with a set of periodic focusing lenses. The multireflecting scheme provides a substantial extension of a flight path (10-100 m) and thus improves resolution, while planar (substantially 2-D) geometry allows retention of a full mass range of analysis. Periodic lenses located in a field free space of the MR-TOF provide a stable confinement of ion motion along the main jig-saw trajectory.
Application of MR-TOF MS to intrinsically continuous ion sources is complicated by an even lower duty cycle of an orthogonal accelerator. A conventional orthogonal acceleration scheme is poorly applicable to an MR-TOF because of two reasons: a) longer flight times (1 ms) and lower repetition rates would reduce the duty cycle by 10 fold; and b) a smaller acceptance of analyzer to ion packet width in the drift direction would require a short length of ion packet (estimated to be below 5 mm for a 50 cm long MR-TOF) which would affect duty cycle again, compared to a conventional accelerator of 20 to 50 mm long. The overall expected duty cycle of MR-TOF with a conventional orthogonal accelerator is expected to be in the order of 1%.
Co-pending U.S. patent application Ser. No. 11/548,556, filed on Oct. 11, 2006, entitled “Multi-Reflecting Time-of-Flight Mass Spectrometer with Orthogonal Acceleration” by Verentchikov et al., the entire disclosure of which is incorporated herein by the reference, suggests several ways of improving duty cycle of an orthogonal accelerator in MR-TOF MS. The incoming ion beam and the accelerator are oriented substantially transverse to the ion path in the MR-TOF, while the initial velocity of the ion beam is compensated by tilting the accelerator and steering the beam for the same angle. To further improve duty cycle, the beam is time-compressed by modulating axial ion velocity with an ion guide. The residence time of ions in the accelerator is improved by either trapping the beam within an electrostatic trap or by slow ion introduction into a radial-confining ion guide that is electrostatic or radiofrequency driven.
3. Combination of ITMS with TOF-MS
A number of examples of tandem trap-TOF mass spectrometers are disclosed in the prior art. In Campbell J. M., Collins B. A. and Douglas D., A New Linear Ion Trap Time-of-Flight System with Tandem Mass Spectrometry Capabilities, Rapid Comm. Mass Spec., 12 (1998) 1463-1474 and in PCT Patent Application Nos. WO 9930350 and WO 0115201, a linear ITMS is coupled with a TOF MS. Ions of interest are isolated and then fragmented within the linear ion trap. A collection of all fragments is axially passed towards a TOF MS with an orthogonal ion injection, preferably in a pulsed manner. Doroshenko et. al. [A Quadrupole Ion Trap/Time-of-flight Mass Spectrometer with a Parabolic Reflectron, J. of Mass Spectrom., v. 33 (1998) 305] employs a 3-D ion trap for isolation and fragmentation of parent ions with subsequent ejection of all fragment ions into the TOF MS. In those examples, the trap is used as any other mass filter (like a quadrupole or magnet sector).
There are several examples of trap-TOF tandems wherein the performance is improved by using ion trap in a mode of mass selective ion ejection. In U.S. Pat. No. 6,504,148, the MSAE ion trap is used to sequentially eject ions in order of their m/z and to inject the ions into a fragmentation cell. The fragments are further analyzed by a time-of-flight mass spectrometer with an orthogonal acceleration. Because of a substantial difference in analysis time (trap scans in 100 ms scale and TOF MS—in 100 μs scale) the method allows so-called parallel MS-MS analysis, i.e., acquisition of fragment spectra for all parent ions.
U.S. Pat. No. 6,504,148 also suggests a direct coupling between an MSAE ion trap and a TOF MS with an orthogonal ion injection in order to improve the overall duty cycle of the TOF MS. Ions are released sequentially in the order of descending m/z. The delay of releasing small ions is compensated by their faster flight time such that ions of all m/z arrive to an orthogonal accelerator simultaneously and at the same ion energy. However, because of limited efficiency of ion ejection in the MSAE trap (<20%) and slow scanning (at least 10-20 ms), the method provides a marginal improvement of duty cycle, if any. Besides, energy and angular spread of ion beam out of the MSAE trap is substantially worse compared to a well-conditioned ion beam behind a collisional dampening ion guide.
Several subsequent attempts have been made using a 3-D ion trap for similar purposes. A mass dependent release from an ion trap into an o-TOF MS is suggested in British Patent No. 2 388 248. A three-dimensional ion trap is suggested as a preferred embodiment. Such a trap generates a substantial energy spread (at least tens of electron volts), high angular spread (a radian if using a 10 eV ion beam), and provides extremely slow scanning (typically longer than 100 ms per decade). Besides, the 3-D trap suffers low efficiency of ion injection into the trap (several percents) and small charge capacity. In a preferred embodiment of U.S. Pat. No. 6,770,871, a 3-D ion trap is coupled to a CID fragmentation cell and a TOF MS for the purpose of parallel MS-MS analysis.
Summarizing the above review, there are multiple applications and embodiments of linear multipoles and linear ion traps. The list comprises (but is not limited to):                Mass spectrometers themselves, also serving as part of tandem mass spectrometers;        Mass spectrometers with sequential ion ejection for parallel MS-MS analysis of fragment spectra for multiple precursors;        Transfer ion guides as an interface in gaseous ion sources;        CID fragmentation cells of tandem mass spectrometers, including accumulating function;        Gaseous ion reaction cells for ion-ion and ion electron reactions and for optical spectroscopy;        Ion guides for intermediate storage and ion accumulation for pulsed operating mass spectrometers, like traps or FTICR MS;        Ion storage device as a source for preparing pulsed ion packets for TOF MS;        Mass selective traps for sequential release of ions into orthogonal accelerator of TOF MS for improving duty cycle of the orthogonal accelerator; and        Ion collecting devices for ion storing after separation in any mass spectrometer.        
There are two distinct types of linear ion traps used so far:                Linear ion guide devices with a good ion beam conditioning but without any mass selection.        Ion traps mass spectrometers which employ resonance ion ejection to reach high mass resolving power. In such traps the ejected ion beam is unstable and has poor angular and energy characteristics, which affects coupling of ion traps to other mass spectrometric devices.        